CN114469945A

CN114469945A - Use of fatty acid synthase inhibitors and pharmaceutical compositions

Info

Publication number: CN114469945A
Application number: CN202011167623.XA
Authority: CN
Inventors: 吴劲梓
Original assignee: Ascletis Bioscience Co Ltd
Current assignee: Ascletis Bioscience Co Ltd
Priority date: 2020-10-28
Filing date: 2020-10-28
Publication date: 2022-05-13

Abstract

The invention provides application of a fatty acid synthase inhibitor shown in a formula (I) or a formula (II) in treating or preventing HBV infection, a pharmaceutical composition containing the fatty acid synthase inhibitor shown in the formula (I) or the formula (II) and other anti-HBV agents, and pharmaceutical application of the fatty acid synthase inhibitor shown in the formula (I) or the formula (II).

Description

Use of fatty acid synthase inhibitors and pharmaceutical compositions

Technical Field

The present invention relates to the field of medicaments for the treatment or prevention of Hepatitis B Virus (HBV) infection. In particular, the present invention relates to the use of fatty acid synthase inhibitors for the treatment or prevention of HBV infection, pharmaceutical compositions comprising fatty acid synthase inhibitors and other anti-HBV agents, and the pharmaceutical use of fatty acid synthase inhibitors.

Background

Hepatitis B Virus (HBV) is a circular double-stranded DNA virus with a partial single-stranded region of the hepatocyte envelope. It is usually transmitted between mother and baby at birth (perinatal transmission) and also through blood or body fluids.

HBV produces covalently closed circular dna (cccdna), secretes HBV surface antigens to suppress the immune system and causes persistent (chronic) infection that is difficult to eradicate. HBV infection is a major public health threat worldwide, with over 2.57 million people chronically infected each year and causing 887,000 deaths (Revill, p.a. et al, Lancet gastroenterol.hepatol,2019,4(7), 545-. More than half of the deaths in Asia Pacific region caused by chronic Hepatitis B Virus (HBV) infection are due to cirrhosis, and about half are cases of hepatocellular carcinoma in this region (Sarin, SK et al, "Langert gastroenteropathy", Hepatol,2020,5(2): 167-. In a summary analysis of 27 studies, the combined estimated prevalence of HBV infection in the general population in china from 2013 to 2017 was reported to be 6.89% (Wang, h.et al BMC infection Dis,2019,19(1), 811).

Currently, treatments for HBV infection are very limited. Approved therapies include nucleotide inhibitors such as tenofovir disoproxil (Viread), tenofovir alafenamide (Vemlidy), entecavir (Baraclude), telbivudine (Tyzeka or Sebivo), lamivudine (Epivir-HBV, Zeffix or hepcodin) and e.g. pegylated interferon (Pegasys). Therefore, new treatments for HBV infection are urgently needed (Fanning, g.c, nat. rev. drug Discov,2019,18(11), 827-844).

Disclosure of Invention

The inventors of the present invention found that the fatty acid synthase inhibitors represented by the formula (I) and the formula (II) have anti-HBV activity. In vitro primary human hepatocyte infection test results show that the fatty acid synthase inhibitors shown in the formula (I) and the formula (II) can effectively inhibit HBV DNA and HBsAg.

Therefore, the invention relates to application of the fatty acid synthase inhibitor shown in the formula (I) or the formula (II) in treating or preventing HBV infection, a pharmaceutical composition containing the fatty acid synthase inhibitor shown in the formula (I) or the formula (II) and other anti-HBV agents, and pharmaceutical application of the fatty acid synthase inhibitor shown in the formula (I) and the formula (II).

Definition of

The following definitions are made for the purpose of explaining the present specification, and where appropriate, singular terms also include the plural and vice versa.

As used herein, the term "pharmaceutically acceptable excipients" may include solvents, dispersion media, coatings, surfactants, antioxidants, preservatives (e.g., antibacterial and antifungal agents), isotonic agents, absorption delaying agents, salts, drug stabilizers, binders, excipients, disintegrants, lubricants, sweeteners, flavoring agents, pigments, and the like, and combinations thereof, known to those skilled in the art. Any conventional carrier is contemplated for use in the therapeutic or pharmaceutical compositions unless incompatible with the active ingredient.

As used herein, the term "hepatitis b virus" or "HBV" refers to a member of the hepadnaviridae family having a small double-stranded DNA genome of about 3,200 base pairs and a hepatocellular tropism. "HBV" includes hepatitis B virus that infects any of a variety of mammalian (e.g., human, non-human primate, etc.) and avian (duck, etc.) hosts. "HBV" includes any known HBV genotype, e.g., serotypes A, B, C, D, E, F and G; any HBV serotype or HBV subtype; any hepatitis B virus isolate; HBV variants, e.g., HBeAg negative variants, drug resistant HBV variants (e.g., lamivudine resistant variants, adefovir resistant variants, tenofovir resistant variants, entecavir resistant variants, etc.); and so on.

As used herein, the term "therapeutically effective amount" refers to the amount of a compound or molecule of the present invention that, when administered to a subject, (i) treats or prevents a particular disease, disorder, or disorder; (ii) alleviating, ameliorating or eliminating one or more symptoms of a particular disease, condition or disorder; or (iii) preventing or delaying the onset of one or more symptoms of a particular disease, condition, or disorder described herein. A therapeutically effective amount will depend upon the compound, the disease state being treated, the severity of the disease being treated, the age and relative health of the subject, the route and form of administration, and the judgment of the attending medical or veterinary.

Unless otherwise indicated, the term "fatty acid synthase inhibitor represented by formula (I) or formula (II)" or "compound of formula (I) or formula (II)" includes fatty acid synthase inhibitors having the structure of formula (I) or formula (II), prodrugs thereof, salts of the compound and/or salts of prodrugs of the compound, hydrates or solvates of the compound, and stereoisomers (including diastereomers and enantiomers), tautomers, isotopically labeled compounds (including deuterium substitutions) and polymorphs of the compound. The term "a compound of formula (I) or formula (II)" encompasses the use of a compound of formula (I) alone, the use of a compound of formula (II) alone, and the use of a compound of formula (I) and a compound of formula (II) together.

Salts included in the term "pharmaceutically acceptable salts" refer to non-toxic salts of the compounds of the present invention. Preferred are alkali metal salts of carboxylic acids, such as sodium, potassium, lithium, calcium, magnesium, aluminum, zinc, N' -dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N-methylglucamine and procaine salts. Other pharmaceutically unacceptable salts may also be useful in the preparation of the compounds of the present invention and should be considered to constitute a further aspect of the invention. Salts of the compounds of the present invention may be prepared by methods known to those skilled in the art. For example, treatment of a compound of the invention with a suitable base or acid in a suitable solvent gives the corresponding salt.

All starting materials, reagents, acids, bases, solvents and catalysts for the synthesis of the compounds of the invention are commercially available or can be produced by organic synthesis methods known to the person skilled in the art. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., such as) provided herein, is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention otherwise claimed.

In one aspect, the present invention provides a method of treating or preventing HBV infection, comprising administering a therapeutically effective amount of a fatty acid synthase inhibitor represented by formula (I) or formula (II), a pharmaceutically acceptable salt, ester, or stereoisomer thereof:

in some embodiments of the present invention, the compounds of formula (I) may be prepared using the following scheme (see in particular the preparation of CN110177551A, p461-464, compound 152, which is incorporated herein by reference):

in some embodiments of the invention, the compounds of formula (II) may be prepared using the following route (see in particular CN105980376B, preparation of p34 compound 2, which is incorporated herein by reference):

according to the method for treating or preventing HBV infection provided by the invention, the fatty acid synthase inhibitor shown in formula (I) or formula (II), and pharmaceutically acceptable salt, ester or stereoisomer thereof (short: the compound shown in formula (I) or formula (II)) can be administered by any route suitable for the condition to be treated. Suitable routes include oral, rectal, nasal, topical (including buccal and sublingual), transdermal, vaginal and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural) and the like. It will be appreciated that the preferred route of administration may vary with, for example, the condition of the subject.

The methods of treating or preventing HBV infection provided by the present invention can be used to adjust the dosage or frequency of administration of a compound of formula (I) or formula (II) during the treatment or prevention, at the discretion of the physician. The dosage frequency of the compound of formula (I) or formula (II) will be determined by the needs of the individual patient and may be, for example, once a day, or twice or more a day. The administration of the compound of formula (I) or formula (II) is continued for a time necessary to treat or prevent HBV infection.

The method for treating or preventing HBV infection provided in accordance with the present invention, wherein the compound of formula (I) or formula (II), a pharmaceutically acceptable salt, ester or stereoisomer thereof, may be used in combination with one or more other anti-HBV agents. Wherein the compound of formula (I) or formula (II) and the other anti-HBV agent may be used in admixture as one pharmaceutical composition or may be co-administered separately as separate pharmaceutical compositions. When in different pharmaceutical compositions, the mode of administration of the compound of formula (I) or formula (II) with other anti-HBV agents may be governed by the same or different routes of administration according to the subject's schedule. Co-administration includes administering a unit dose of a compound of formula (I) or formula (II) before or after administering a unit dose of one or more other anti-HBV agents. In some embodiments, the compound of formula (I) or formula (II) may be administered within seconds, minutes, or hours of administration of the one or more other anti-HBV agents. In other embodiments, a unit dose of a compound of formula (I) or formula (II) is administered first, followed by administration of one or more other anti-HBV agents within seconds, minutes, or hours.

The method for treating or preventing HBV infection provided by the present invention, wherein the other anti-HBV agent may be any anti-HBV agent except the compound of formula (I) and formula (II), which is not particularly limited in the present invention. For example, the additional anti-HBV agent may be selected from antisense oligonucleotides targeted to viral mRNA, short interfering rnas (sirnas), B and T lymphocyte attenuation inhibitors, CCR2 chemokine antagonists, compounds targeted to HBcAg, compounds targeted to hepatitis B core antigen (HBcAg), covalent closed circular DNA (cccdna) inhibitors, cyclophilin inhibitors, cytokines, endonuclease modulators, epigenetic modifiers, gene modifiers or editors, farnesol X receptor agonists, hepatitis B surface antigen (HBsAg) inhibitors, HBsAg secretion or assembly inhibitors, HBV antibodies, HBV DNA polymerase inhibitors, HBV replication inhibitors, HBV RNAse inhibitors, HBV vaccines, HBV viral entry inhibitors, HBx inhibitors, hepatitis B structural protein modulators, hepatitis B virus E antigen inhibitors, hepatitis B virus replication inhibitors, hepatitis B virus structural protein inhibitors, IL-2 agonists, IL-7 agonists, immunomodulators, ribonucleotide reductase inhibitors, interferon agonists, interferon alpha 1 ligands, interferon alpha 2 ligands, interferon alpha 5 ligand modulators, interferon alpha ligands, interferon alpha ligand modulators, interferon alpha receptor ligands, interferon beta ligands, interferon receptor modulators, interleukin 2 ligands, lysine demethylase inhibitors, microRNA (miRNA) gene therapy agents, B7-H3 modulators, B7-H4 modulators, CD 160 modulators, CD161 modulators, CD27 modulators, CD47 modulators, CD70 modulators, GITR modulators, TIGIIT modulators, Tim-4 modulators, sodium taurocholate cotransporter polypeptide (NTCP) inhibitors, natural killer cell receptor 2B4 inhibitors, NOD2 gene stimulators, nucleoprotein inhibitors, nuclear protein inhibitors, and the like, Nucleoprotein modulators, PD-1 inhibitors, PD-L1 inhibitors, PEG-interferon lambda, peptidyl prolyl isomerase inhibitors, retinoic acid inducible gene 1 agonists, reverse transcriptase inhibitors, ribonucleic acid mitigators inhibitors, RNA DNA polymerase inhibitors, short synthetic hairpin RNA (sshrna), agonists of interferon gene agonists (STING), NOD 1 agonists, T cell surface glycoprotein CD28 inhibitors, TLR-3 agonists, TLR-7 agonists, TLR-8 agonists, TLR-9 agonists, TLR9 gene stimulators, TOLL-like receptor (TLR) modulators, viral ribonucleotide reductase inhibitors, zinc finger nucleases, or synthetic nucleases (TALENs), and the like.

In a preferred embodiment of the invention, the additional anti-HBV agent is selected from one or more of HBV vaccines, HBV DNA polymerase inhibitors, immunomodulators, Toll-like receptor (TLR) modulators, interferon alpha receptor ligands, farnesol X receptor agonists, hepatitis b surface antigen (HBsAg) inhibitors, cyclophilin inhibitors, HBV viral entry inhibitors, antisense oligonucleotides targeted to viral mRNA, short interfering rna (sirna) and ddRNAi endonuclease modulators, ribonucleotide reductase inhibitors, HBV E antigen inhibitors, covalently closed circular DNA (ccc) inhibitors, HBV antibodies, CCR2 chemokine antagonists, retinoic acid inducible gene 1 agonists, NOD2 agonists, PD-1 inhibitors, PD-L1 inhibitors, KDM inhibitors, and HBV replication inhibitors.

In one embodiment, the other anti-HBV agent is a nucleotide. Examples of HBV DNA polymerase inhibitors include adefovir (HEPSERA), Atrocitabine (EMTRIVA), and TransTenofovir disoproxil fumarate

Tenofovir alafenamide, tenofovir disoproxil, tenofovir alafenamide fumarate, tenofovir disoproxil, tenofovir alafenamate, tenofovir octadecyloxyethyl ester, CMX-157, besofovir (besifovir), entecavir

Entecavir maleate, Telbivudine (TYZEKA), peradfovir, Devudine, ribavirin, Lamivudine (EPIV)

) Azidophosphine (phosphazide), famciclovir, foselin, metacavir, SNC-019754, FMCA, AGX-1009, AR-II-04-26, HIP-1302, tenofovir disoproxil aspartate, tenofovir disoproxil orotate, and HS-10234. Other examples of HBV DNA polymerase inhibitors include feloxivir.

In a particular embodiment, the compounds of formula (I) of the present invention are combined with entecavir or tenofovir.

In another embodiment, the other anti-HBV agent is an immunomodulatory agent. Examples of such immune modulators include the TLR agonists RO7020531, GS-9620, GS-9688. Examples of immunomodulators also include PD-1 inhibitors, such as nivolumab, pembrolizumab, pidilizumab, BGB-108, SHR-1210, PDR-001, Sasanlimab, PF-06801591, IBI-308, gemipilimumab, Camlizumab, Similizumab, Sidilizumab, Tislelizumab, BGB-A317, BCD-100, Cetilizumab (Cetrelizab), JNJ-63723283, Zimberilumab (GLS-010, WBP-3055), Batilizumab (Balstrilizab) (AGEN2034), and doslizumab (DORTSTAIRLAb) (TSR-042). Examples of immunomodulators also include PD-L1 inhibitors, such as Attributumab (atelizumab) (RG-7446), Avelumab (avelumab), BGB-A333, Devolumab (durvalumab), CX-072, GX-P2, and envolumab (KN035, ASC 022). The PD-L1 inhibitor may also be a small molecule inhibitor, such as GS-4224 and INCB 086550.

In a specific embodiment, the compound of formula (I) is combined with envoriximab.

In yet another embodiment, the other anti-HBV agent is a farnesoid X receptor agonist. Examples of such farnesoid X receptor agonists include AKN-083, Cilofexor, EDP-305, EYP-001, MET-409, Terns-101 and Tropifexor.

In a particular embodiment, the compounds of formula (I) according to the invention are combined with the fatty acid synthase inhibitors TVB-2640 and/or TVB-3567.

In yet another embodiment, the other anti-HBV agent is a common or long-acting interferon. Examples of the interferon include pegin, pirocin (Pegasys), pelargoni (PEG-INTRON)

In a specific embodiment, the compound of formula (I) is combined with pirocin.

In yet another embodiment, the other anti-HBV agent is an HBV vaccine. The HBV vaccine comprises prevention and treatment vaccine. Examples of the HBV prophylactic vaccine include Vaxelis, Hexaxim, Heplinav, Mosquirix, DTwP-HBV vaccine, Bio-Hep-B, D/T/P/F1BV7M (LBVP-0101; LBVW-0101), DTwP-Hepb-FIib-IPV vaccine, Heberpenta L, DTwP-HepB-Hib, V-419, CVI-HBV-001, Tetrabhay, hepatitis B prophylactic vaccine (Advax Super D), Hepatrol-07, GSK-223192A, B-B, C-H-L-H-L,

Recombinant hepatitis B vaccine (intramuscular injection, Coretat biological product), recombinant hepatitis B vaccine (Hansenula polymorpha, intramuscular, Hualan bioengineering company), recombinant hepatitis B surface antigen vaccine, Bimmugen, Euforvac, Eutravac, anrix-DTaP-IPV-Hep B, HBAI-20, Infanrix-DT aP-IPV-Hep B-Hib, Pentobio Vaksin DTP-HB-Hib, Comvac 4, Twinrix, Euvax-B, Tritanrix HB, Infanrix Heb, Comvax, DTP-Hib-HBV vaccine, DTP-HBV vaccine, Hebergiova HB, and the like,Trivac HB, GerVax, DTwP-Hep B-Hib vaccine, Bileft (Bilive), HepavaxGene, SUPERVAX, Comvac5, Shanvac-B, Hebsulin, Recombivax HB, Revac B mcf, Revac B +, Fendrix, DTwP-HepB-Hib, DNA-001, Shan5, Shan6, HBsAG vaccine, HBI pentavalent vaccine, LBVD, Infanrix HeXa and DTaP-rHB-Hib vaccine.

In a specific embodiment, a compound of formula (I) of the invention is combined with one or more of ABX203, AIC 649, INO-1800, HB-110, TG1050, HepTcell, VR-CHB01, VBI-2601 and CAG-201.

In yet another embodiment, the additional anti-HBV agent is an antisense oligonucleotide (ASO) targeted to viral mRNA. Examples of antisense oligonucleotides include Ionis-HBVRx and Ionis-HBV-LRx.

In yet another embodiment, the other anti-HBV agent is a short interfering rna (sirna). Examples of short interfering RNAs include JNJ-3989(ARO-HBV), Vir-2218(ALN-HBV02) and DCR-HBVS.

In yet another embodiment, the additional anti-HBV agent is a hepatitis surface antigen (HBsAg) inhibitor. Examples of the HBsAg inhibitor include HBF-0259, PBHBV-001, PBHBV-2-15, PBHBV-2-1, REP-9AC, REP-9C, REP-9, REP-2139, REP-2l39-Ca, REP-2165, REP-2055, REP-2163, REP-2165, REP-2053, REP-203 and REP-006, REP-9AC, and inhibitors against PAPD 57.

In yet another embodiment, the additional anti-HBV agent is an HB viral entry inhibitor, such as Myrcludex B, herplap peptide, or an antibody targeting preS.

In yet another embodiment, the additional anti-HBV agent is a capsid inhibitor. Examples of HBsAg inhibitors include ABI-H0731, ABI-H2158, ABI-H3733, CB-HBV-001, JNJ-6379, JNJ-0440, QL-007, RG-7907, and RO 7049389.

In a most preferred embodiment of the invention, the additional anti-HBV agent is selected from one or more of entecavir, tenofovir, entinostumab and pirocin.

On the other hand, the invention also provides application of the fatty acid synthase inhibitor shown in the formula (I) or the formula (II), and pharmaceutically acceptable salt, ester or stereoisomer thereof in preparing anti-HBV medicines. Wherein the fatty acid synthase inhibitor represented by the formula (I) or the formula (II), a pharmaceutically acceptable salt, ester or stereoisomer thereof is as defined above.

According to the present invention, there is provided a use wherein the anti-HBV drug comprises a fatty acid synthase inhibitor represented by formula (I) or formula (II), a pharmaceutically acceptable salt, ester or stereoisomer thereof, and one or more other anti-HBV agents as active ingredients. Wherein the other anti-HBV agent is as defined above.

In still another aspect, the present invention provides an anti-HBV pharmaceutical composition, which comprises a therapeutically effective amount of a fatty acid synthase inhibitor represented by formula (I) or formula (II), a pharmaceutically acceptable salt, ester, or stereoisomer thereof, and one or more other anti-HBV agents, and pharmaceutically acceptable excipients. Wherein the fatty acid synthase inhibitor represented by the formula (I) or the formula (II), a pharmaceutically acceptable salt, ester or stereoisomer thereof is as defined above. Wherein the other anti-HBV agent is as defined above.

The anti-HBV pharmaceutical compositions of the present invention are suitable for oral, rectal, nasal, topical (including buccal and sublingual), transdermal, vaginal and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural) administration and the like. The particular mode of administration will depend on the nature and severity of the condition being treated and on the nature of the active ingredient. The pharmaceutical compositions may conveniently be presented in unit dosage form and may be prepared by any of the methods well known to those skilled in the art of pharmacy.

The pharmaceutical compositions of the present invention are suitable for various routes of administration, including oral administration. The compositions may be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. Such methods include the step of combining the active ingredient (e.g., a fatty acid synthase inhibitor of the present invention represented by formula (I) or formula (II), or a pharmaceutically acceptable salt thereof) with one or more pharmaceutically acceptable excipients. The compositions can be prepared by uniformly and intimately bringing the active ingredient into association with liquid excipients or solid excipients or both, and then, if necessary, shaping the product. Compositions suitable for oral administration described herein may be presented in discrete units (unit dosage forms) including, but not limited to, capsules, cachets, or tablets each containing a predetermined amount of the active ingredient. In one embodiment, the pharmaceutical composition is a tablet.

The fatty acid synthase inhibitor represented by the formula (I) or the formula (II) may be administered to a subject in an effective amount. The amount of active ingredient that can be combined with the inactive ingredients to produce a dosage form can vary depending upon the intended subject of treatment and the particular mode of administration. For example, in some embodiments, a dosage form for oral administration to a human may contain from about 1 to 1000mg of the active material formulated with an appropriate and convenient amount of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutically acceptable excipient is from about 5% to about 95% of the total composition.

The dosage or frequency of administration of the compounds of formula (I) or formula (II) of the invention may be adjusted during the course of treatment, based on the judgment of the administering physician. The dosage frequency of a compound of formula (I) or formula (II) will be determined by the individual patient's requirements and may be, for example, once a day or twice or more a day, or more. The administration of the compound is continued for the time required to treat HBV infection.

Drawings

In order to more clearly explain technical solutions in embodiments of the present invention, drawings for describing embodiments of the present invention will be briefly described below. It is to be understood that the drawings in the following description are of some embodiments of the invention only.

FIG. 1 is an EC50 curve for HBV DNA inhibition in PHH cells;

FIG. 2 is an EC50 curve for HBsAg inhibition in PHH cells;

FIG. 3 is an EC50 curve of HBsAg inhibition in HepG2-NTCP cells;

FIG. 4 is an EC50 curve of HBeAg inhibition in HepG2-NTCP cells.

Detailed Description

The invention is further illustrated with reference to the following examples. It should be noted that the following examples are only for illustration and are not intended to limit the present invention. Various modifications of the invention in light of the teachings herein will be suggested to one skilled in the art and are to be included within the scope of the appended claims.

Example 1: preparation of Compounds of formula (I)

(1) Preparation of Compound 1b (methyl 4-bromo-2-methylbenzoate)

Sulfuric acid (2.0ml) was added dropwise over about 3 minutes to a solution of 4-bromo-2-methylbenzoic acid (5.11g, 23.8mmol, 1.0 equiv) in methanol (25ml) (slightly exothermic). The resulting mixture was refluxed for 4 hours. After cooling to room temperature, the reaction mixture was quenched with saturated NaHCO₃The aqueous solution (100ml) was carefully quenched (note: large gas evolution) and extracted with dichloromethane (200ml × 1 followed by 50ml × 1). The combined organic phases were washed with brine/saturated NaHCO₃The mixture of (9: 1) (50ml) was washed and dried (Na)₂SO₄) And concentrated under reduced pressure to obtain compound 1b (5.28g, yield 97%) as a colorless oil.

¹H NMR(400MHz,CDCl₃):δ7.78(d,J＝8.0Hz,1H),7.42(d,J＝1.6Hz,1H),7.38(dd,J＝1.6Hz,1H),3.89(s,3H),2.58(s,3H)。

(2) Preparation of Compound 1c (methyl 4-cyclobutyl-2-methylbenzoate)

Cyclobutylzinc (II) bromide (50ml, 0.5M in THF, 25.0mmol) was added to methyl 4-bromo-2-methylbenzoate (5.2g, 22.7mmol) and PdCl₂(dppf)CH₂Cl₂(1.85g, 2.27mmol) in a mixture. The mixture was degassed and the flask was filled with argon via balloon. The mixture was heated at 65 ℃ for 24 hours under argon. The mixture was cooled to 0 ℃ and quenched with water (10 ml). The mixture was diluted with EtOAc (200mL) and washed successively with water and brine. EtOAc layer was dried (Na)₂SO₄) Concentrated under reduced pressure and using a column (Silica gel) chromatography (hexane: EtOAc 30: 1 to 20: 1). Yield: 4.1g, clear oil, 89.1% yield.

¹H NMR (400MHz, chloroform-d) < delta > 7.86(d,1H),7.12 to 7.02(m,2H),3.88(s,3H),3.59 to 3.48(m,1H),2.59(s,3H),2.35(m,2H),2.22 to 1.96(m,3H),1.86 to 1.84(m, 1H).

(3) Preparation of Compound 1d (methyl 4-cyclobutyl-5-iodo-2-methylbenzoate)

N-iodosuccinimide (3.52g, 15.6mmol) was added portionwise to a solution of methyl 4-cyclobutyl-2-methylbenzoate (3.2g, 15.6mmol) in concentrated sulfuric acid (25ml) at 0 ℃. The mixture was stirred at 0 ℃ for 30 minutes and at room temperature for 2 hours. The mixture became extremely thick. The mixture was cooled to 0 ℃ again and MeOH (30ml) was added. The mixture was heated at 60 ℃ for 2 hours. Methanol was removed under reduced pressure and the residue poured into ice water (100 ml). The mixture was extracted with EtOAc. The combined organic layers were washed with brine and 1N NaHCO₃The aqueous solution is washed successively (note: large gas evolution), dried (Na)₂SO₄) And concentrated. The residue was purified using column (silica gel) chromatography (hexane: EtOAc 30: 1 to 20: 1). Yield: 4.17g, light yellow oil, yield 81%.

¹H NMR (400MHz, chloroform-d) < delta > 8.33(s,1H),7.14(s,1H),3.87(s,3H),3.67-3.54(m,1H),2.57(s,3H),2.51-2.40(m,2H),2.14-1.97(m,3H),1.82-1.79(m, 1H).

(4) Preparation of Compound 1e (methyl 5-cyano-4-cyclobutyl-2-methylbenzoate)

Methyl 4-cyclobutyl-5-iodo-2-methylbenzoate (4.17g, 12.64mmol), Zn (CN)₂(2.96g, 25.21mmol) and Pd (PPh)₃)₄A mixture of (0.73g, 0.63mmol) in DMF (30ml) was degassed and argon was used via balloonThe flask was filled with gas. The mixture was heated at 100 ℃ overnight under argon. After cooling to ambient temperature, the mixture was taken up in saturated FeSO₄Aqueous solution (20ml) was quenched and diluted with EtOAc (200 ml). The pale green solid was removed by filtration through celite. The filtrate was partitioned between water and EtOAc. The EtOAc layer was washed with brine and dried (Na)₂SO₄) And concentrated. The residue was purified using column (silica gel) chromatography (hexane: EtOAc 30: 1 to 20: 1). Yield: 2.55g of white solid, yield 88%.

¹H NMR (400MHz, chloroform-d) < delta > 8.16(s,1H),7.28(s,1H),3.90(s,3H),3.86-3.82(m,1H),2.68(s,3H),2.55-2.45(m,2H),2.27-2.04(m,3H),1.89-1.87(m, 1H).

(5) Preparation of Compound 1f (methyl 5-thiocarbamoyl-4-cyclobutyl-2-methylbenzoate)

To a round bottom flask were added methyl 5-cyano-4-cyclobutyl-2-methylbenzoate (3.63g, 0.015mol), diethyl dithiophosphate O, O' -ester (10ml) and water (1 ml). The reaction mixture was heated to 80 ℃ for 3 hours (note: significant gas evolution occurred; this reaction and all other reactions described herein should be carried out in a well-ventilated fume hood). After cooling to room temperature, the reaction mixture was partitioned between ethyl acetate (50ml) and water (50 ml). The combined organic layers were washed with NaHCO₃The mixture was washed successively with saturated aqueous solution (50ml) and brine (50ml) over Na₂SO₄Dried and concentrated in vacuo. By SiO₂Purification by flash chromatography (hexane/ethyl acetate 80/20 to 50/50) gave methyl 5-thiocarbamoyl-4-cyclobutyl-2-methylbenzoate (3.06g, 78% yield) as a yellow solid.

m/z(ES+)264(M+H)⁺。¹H NMR(400MHz,CDCl₃):δ7.93(s,1H),7.82(s,1H),7.26(s,1H),6.92(s,1H),4.19(m,1H),3.89(s,3H),2.64(s,3H),2.40(m,2H),2.29-2.15(m,2H),2.12-2.00(m,1H),1.95-1.84(m,1H)。

(6) Preparation of the Compound 1g (methyl 4-cyclobutyl-5- (imino (methylthio) methyl) -2-methylbenzoate)

To a round-bottom flask was added THF (10ml) containing methyl 5-thiocarbamoyl-4-cyclobutyl-2-methylbenzoate (861mg, 3.27 mmol). Methyl iodide (MeI) (912mg, 6.42mmol) was added dropwise and the reaction mixture was stirred at room temperature for 7 hours. The reaction mixture was concentrated in vacuo and passed through SiO₂Purification by flash chromatography (ethyl acetate to ethyl acetate/methanol ═ 95/5) gave methyl 4-cyclobutyl-5- (imino (methylthio) methyl) -2-methylbenzoate as a pale yellow oil (807mg, 89% yield).

m/z(ES+)278(M+H)⁺。¹H NMR(400MHz,DMSO-d₆):δ7.67(s,1H),7.40(s,1H),3.88-3.71(m,4H),2.57(s,3H),2.44(s,3H),2.22-2.19(m,2H),2.12(m,2H),.1.98-1.86(m,1H),1.82-1.70(m,1H)。

(7) Preparation of compound 1H (methyl 4-cyclobutyl-2-methyl-5- (5-methyl-4H-1, 2, 4-triazol-3-yl) benzoate)

To a round-bottom flask was added a solution of 4-cyclobutyl-5- (imino (methylthio) methyl) -2-methylbenzoic acid methyl ester (556mg, 0.002mol) and acethydrazide (223mg, 0.003mol) in 6ml of acetic acid. The reaction mixture was heated to 90 ℃ for 3 hours. After cooling to room temperature, the reaction mixture was partitioned between water (50ml) and ethyl acetate (50 ml). The organic layer was washed with brine (2X 50ml) and Na₂SO₄Dried and concentrated in vacuo. Via SiO₂Purification by flash chromatography (hexane/ethyl acetate 50/50 to 30/70) gave the title compound as a white solid (243mg, 43% yield).

m/z(ES+)286(M+H)⁺。¹H NMR(400MHz,CDCl₃):δ8.23(s,1H),7.32(s,1H),4.24-4.05(m,1H),3.89(s,3H),2.69(s,3H),2.54(s,3H),2.23-2.20(m,2H),2.16-2.05(m,2H),2.05-1.88(m,1H),1.88-1.71(m,1H)。

(8) Preparation of Compound 1i (4-cyclobutyl-2-methyl-5- (5-methyl-4H-1, 2, 4-triazol-3-yl) benzoic acid)

To a solution of methyl 4-cyclobutyl-2-methyl-5- (5-methyl-4H-1, 2, 4-triazol-3-yl) benzoate (240mg, 0.842mmol) in methanol (5ml) was added aqueous NaOH solution (6ml, 1M). The resulting mixture was heated to 50 ℃ for 6 hours. After cooling to ambient temperature, the reaction mixture was acidified to pH 2 with 1N HCl and extracted with ethyl acetate (3 × 50 ml). The combined organic layers were washed with brine (50ml) and Na₂SO₄Dried and concentrated in vacuo to give 4-cyclobutyl-2-methyl-5- (5-methyl-4H-1, 2, 4-triazol-3-yl) benzoic acid (260mg, quant.) as a white solid.

m/z(ES+)272(M+H)⁺。

(9) Preparation of the Compound 1(4- (1- (4-cyclobutyl-2-methyl-5- (5-methyl-4H-1, 2, 4-triazol-3-yl) benzoyl) piperidin-4-yl) benzonitrile, i.e. a Compound of formula (I) according to the invention)

To a solution of 4-cyclobutyl-2-methyl-5- (5-methyl-4H-1, 2, 4-triazol-3-yl) benzoic acid (260mg, 0.95mmol) in DMF (4ml) was added 4- (piperidin-4-yl) benzonitrile hydrochloride (232mg, 1.045mmol), EDC (272mg, 1.425mmol), HOBt (39mg, 0.285mmol) and DIEA (367.7mg, 2.85 mmol). The resulting mixture was stirred at room temperature for 16 hours. NaHCO for the mixture₃Saturated aqueous solution (20ml) was quenched and extracted with ethyl acetate (2X 50 ml). The combined organic layers were washed with brine (50ml) and Na₂SO₄Dried, filtered and concentrated in vacuo. Via SiO₂Column chromatography (dichloromethane/methanol ═ 95/5) afforded 4- (1- (4-cyclobutyl-2-methyl-5- (5-methyl-4H-1, 2, 4-triazole as a white solid-3-yl) benzoyl) piperidin-4-yl) benzonitrile (193mg, yield 44%).

m/z(ES+)440(M+H)⁺。

¹H NMR(300MHz,CD₃OD delta 7.69(d, J-5.4 Hz,2H),7.56-7.30(m,4H),1 proton masked by the methanol solvent peak, 4.10-3.98(m,1H),3.64(t, J-10.7 Hz,1H),3.33-3.21(m,1H),3.00(t, J-8.9 Hz,2H),2.58(s,3H),2.48 and 2.38(2 singlet, amide rotamers, ArCH, R₃,3H),2.28-1.92(m,6H),1.92-1.55(m,4H)。

1H NMR(400MHz,DMSO-d6):δ13.66(s,1H),7.77(d,J＝8.0Hz,2H),7.62-7.34(m,4H),4.78-4.63(m,1H),4.31(br s,1H),3.45(br s,1H),3.15(app t,J＝12.3Hz,1H),2.99-2.78(m,2H),2.44-1.80(m,12H),1.80-1.37(m,4H)。

Example 2: preparation of the Compound of formula (II)

(1) Preparation of Compound 2b (3-formyl-4-methylbenzoic acid)

In a 3000ml three-neck round bottom flask, purged and maintained with a nitrogen inert atmosphere, was placed a solution of 3-bromo-4-methylbenzoic acid (100g, 465mmol, 1.00 eq.) in tetrahydrofuran (1500 ml). n-BuLi (2.5M in THF) (411ml, 1023mmol, 2.20 equiv.) was added dropwise thereto at-78 deg.C and stirred for 30 min. N, N-dimethylformamide (101g, 1.38mol, 3.00 equiv.) was added to the reaction at-78 ℃. The resulting solution was stirred in a liquid nitrogen bath at-78 ℃ for 30min and then quenched with 1000ml of water. The aqueous layer was washed with 1000ml of ethyl acetate and the pH of the solution was adjusted to 3-4 with 6N hydrogen chloride. The solid was collected by filtration and dried in an oven to give 45g of a yellow solid, i.e., 3-formyl-4-methylbenzoic acid, yield 59%.

(2) Preparation of Compound 2c (3- (1-hydroxypropyl) -4-methylbenzoic acid)

In a 2000ml round bottom flask purged and maintained with a nitrogen inert atmosphere was placed a solution of 3-formyl-4-methylbenzoic acid (40g, 243.67mmol, 1.00 eq.) in THF (1000 ml). To this was added dropwise magnesium (ethyl) bromide (244ml, 3N in ether, 3.00 eq.) at 0 ℃. The resulting solution was stirred at 20 ℃ for 2-3h and then with 500ml NH₄And (4) quenching by using a Cl saturated solution. The pH of the solution was adjusted to 4-5 with hydrogen chloride (6 mol/L). The aqueous phase is extracted with 2 × 500ml of ethyl acetate and the combined organic layers are dried over anhydrous sodium sulfate and concentrated in vacuo. 50g of crude 3- (1-hydroxypropyl) -4-methylbenzoic acid are obtained as a yellow solid.

(3) Preparation of compound 2d (4-methyl-3-propionylbenzoic acid)

A2000 mL round bottom flask was charged with a solution of crude 3- (1-hydroxypropyl) -4-methylbenzoic acid (50g, 1.00 equiv.) in dichloromethane (1000mL), Dess-Martin Periodinane (Dess-Martin oxidant) (131g, 309.28mmol, 1.20 equiv.). The resulting solution was stirred at 25 ℃ for 2h and then over 500ml 2M Na₂S₂O₃(aqueous solution) quenching. The solid is filtered off, the aqueous phase is extracted with 2X 500ml of ethyl acetate and concentrated in vacuo. 45g (crude) of 4-methyl-3-propionylbenzoic acid are obtained as yellow solid.

(4) Preparation of compound 2e (methyl 4-methyl-3-propionylbenzoate)

In a 2000ml round bottom flask purged and maintained with a nitrogen inert atmosphere, a solution of crude 4-methyl-3-propionylbenzoic acid (45, 1.00 equivalents) in methanol (1000ml) was placed. Sulfuric acid (45.9g, 468.4mmol, 2.00 equiv.) was added dropwise thereto. The resulting solution was stirred in an oil bath at 80 ℃ for 4h, then concentrated under vacuum. The reaction was quenched with 500ml water/ice. The aqueous phase is extracted with 2X 500ml of ethyl acetate. The combined organic layers were washed with 1 × 200ml sodium bicarbonate (saturated), 2 × 200ml brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was applied to a silica gel column with ethyl acetate/petroleum ether (1/50). 22g (yield 46%) methyl 4-methyl-3-propionylbenzoate are obtained as pale yellow solid.

(5) Preparation of compound 2f (methyl 3- (3-methoxy-2-methyl-3-oxopropanoyl) -4-methylbenzoate)

To a solution of methyl 4-methyl-3-propionylbenzoate (5.0g, 24.24mmol, 1.00 equiv.) in dimethyl carbonate (70ml) was added sodium hydride (60%) (1.5g, 62.50mmol, 1.50 equiv.) in portions at 0 ℃ and stirred under nitrogen at 90 ℃ for 2.0 h. The reaction was then quenched with 50ml NH₄Cl (sat) and extracted with 3X 100ml ethyl acetate. The organic phase is washed with 2X 100ml brine and dried over anhydrous sodium sulfate and then concentrated in vacuo to give 6.8g (crude) of methyl 3- (3-methoxy-2-methyl-3-oxopropanoyl) -4-methylbenzoate as a yellow oil.

(6) Preparation of compound 2g (methyl 4-methyl-3- (4-methyl-5-oxo-2, 5-dihydro-1H-pyrazol-3-yl) benzoate)

To a solution of methyl 3- (3-methoxy-2-methyl-3-oxopropanoyl) -4-methylbenzoate (3.3g, 12.49mmol, 1.00 eq) in ethanol (30ml) was added NH₂NH₂.H₂O (98%) (1.33g, 26.66mmol, 2.00 equiv.). The resulting solution was stirred at reflux for 4.0h, then concentrated under vacuum. The residue was purified by silica gel chromatography using CH₂Cl₂MeOH (50/1 to 40/1) as eluent gave 1.8g (yield 59%) of methyl 4-methyl-3- (4-methyl-5-oxo-2, 5-dihydro-1H-pyrazol-3-yl) benzoate as a pale yellow solid.

(7) Preparation of the Compound 2H (methyl 3- (3- (2-hydroxyethoxy) -4-methyl-1H-pyrazol-5-yl) -4-methylbenzoate)

To a solution of methyl 4-methyl-3- (4-methyl-5-oxo-2, 5-dihydro-1H-pyrazol-3-yl) benzoate (40g, 163mmol, 1.00 eq) in DMA (800ml) were added potassium carbonate (112g, 813mmol, 5.00 eq) and 2-bromoethane-1-ol (141g, 1138mmol, 7.00 eq). The mixture was stirred at 25 ℃ for 4H and then with 1000ml H₂And (4) diluting with oxygen. The aqueous phase is extracted with 5X 1000ml of ethyl acetate and the combined organic layers are washed with 2X 1000ml of brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was applied to a silica gel column using ethyl acetate/petroleum ether (1:10 to 1:1) as eluent to give 30g (yield 64%) of methyl 3- (3- (2-hydroxyethoxy) -4-methyl-1H-pyrazol-5-yl) -4-methylbenzoate as a pale yellow oil.

(8) Preparation of compound 2i (3- (3- (2-hydroxyethoxy) -4-methyl-1H-pyrazol-5-yl) -4-methylbenzoic acid)

To a solution of methyl 3- (3- (2-hydroxyethoxy) -4-methyl-1H-pyrazol-5-yl) -4-methylbenzoate (30g, 103mmol, 1.00 eq) in methanol (500ml) was added a solution of sodium hydroxide (41g, 1025mmol, 10.0 eq) in water (300 ml). The mixture was stirred at room temperature for 2 h. The resulting mixture was concentrated in vacuo and the pH of the solution was adjusted to 4-5 with hydrogen chloride (2 mol/L). The solid was collected by filtration. 20g (yield 71%) of 3- (3- (2-hydroxyethoxy) -4-methyl-1H-pyrazol-5-yl) -4-methylbenzoic acid are obtained as a pale yellow solid.

(9) Preparation of the Compound 2(4- (1- (3- (3- (2-hydroxyethoxy) -4-methyl-1H-pyrazol-5-yl) -4-methylbenzoyl) azetidin-3-yl) benzonitrile, i.e., the Compound of formula (II) of the present invention

To a solution of 3- (3- (2-hydroxyethoxy) -4-methyl-1H-pyrazol-5-yl) -4-methylbenzoic acid (20.0g, 72.5mmol, 1.00 eq) in DCM (500ml) were added EDCI (16.7g, 87.0mmol, 1.20 eq), 4-dimethylaminopyridine (1.77g, 14.5mmol, 0.20 eq), DIEA (23.4g, 181mmol, 2.50 eq) and 4- (azetidin-3-yl) benzonitrile hydrochloride (15.5g, 79.7mmol, 1.10 eq). The resulting solution was stirred at room temperature overnight. The resulting solution was taken up in 500ml of H₂And (4) diluting with O. The resulting solution was extracted with 3X 500ml ethyl acetate and the combined organic layers were extracted with 2X 500ml NH₄Cl (saturated), 2 × 500ml brine, and dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography using CH₂Cl₂MeOH (50/1 to 30/1) as eluent gave 21.0g (67% yield) of 4- (1- (3- (3- (2-hydroxyethoxy) -4-methyl-1H-pyrazol-5-yl) -4-methylbenzoyl) azetidin-3-yl) benzonitrile as a white solid.

m/z(ES+)417.3(M+H)⁺。

Biological examples

Determination of Activity of Compound 1 and Compound 2 in HBV cells

PHH (primary human hepatocytes) analysis: cell lines and compound treatments

PHH cells were cultured at 1.32X 10⁵The density of cells/well was seeded in 48-well plates. The date of seeding of PHH cells was defined as day 0. PHH cells were infected with 1600 GE/cell HBV (type D) on day 1. The media containing the compounds were refreshed on

days

2,4, 6 and 8. Day 9 supernatants were collected and analyzed for HBV DNA by qPCR and HBsAg by ELISA.

Compounds were tested at 10000.0, 3000.0, 1000.0, 300.0, 100.0, 30.0 and 10.0nM and Entecavir (ETV) was tested at 0.2000, 0.0667, 0.0222, 0.0074, 0.0025, 0.0008 and 0.0003 nM. 1% DMSO was used as a non-treatment control.

Determination of HBV DNA and HBsAg

DNA in the culture supernatant was isolated using QIAamp 96DNA blood kit according to the manual and quantified by qPCR. DNA was extracted using 80. mu.l of a sample of the culture supernatant. The elution volume was 120. mu.l. The PCR mix (8 μ Ι/well) and sample (2 μ Ι/well) or plasmid standard (2 μ Ι/well) were added to 384-well optical reaction plates and performed using the following procedure: 10 minutes at 95 ℃ and then 40 cycles of 15 seconds at 95 ℃ and 1 minute at 60 ℃.

The content of HBsAg was determined using Chemilurinecence Aparatu, with reference to the Antu HBsAg ELISA kit instructions.

Dose response curve

HBV DNA inhibition (%) (HBV DNA copy number of 1-compound group sample/HBV DNA copy number of DMSO group) × 100

HBsAg inhibition (%) was ═ 100 (1-HBsAg value of sample/DMSO control HBsAg value) × 100

Analysis of results

As shown in fig. 1 and 2, wherein fig. 1 is an EC50 curve for suppressing HBV DNA in PHH cells; fig. 2 is an EC50 curve for HBsAg inhibition in PHH cells. In the PHH assay, compounds 1 and 2 had dose-dependent inhibition of extracellular HBV DNA and HBsAg. As a control, ETV showed significant inhibition of HBV DNA, but no significant inhibition of HBsAg.

HepG2-NTCP cell assay: cell lines and compound treatments

HepG2-NTCP cells at 7.5X 10⁴The density of cells/well was seeded in 48-well plates. The date of inoculation of HepG2-NTCP cells was defined as day 0. HepG2-NTCP cells were infected with 2000 GE/cell HBV (type D) on day 2. The culture medium containing the compound was changed once on day 3 and day 6. On day 9, cell supernatants were collected for detection of HBeAg (ELISA) and HBsAg (ELISA).

Compounds were tested at 10000.0, 3000.0, 1000.0, 300.0, 100.0, 30.0 and 10.0nM and Entecavir (ETV) was tested at 5.000, 1.250, 0.313, 0.078, 0.020, 0.005 and 0.001 nM. 1% DMSO was used as a non-treatment control.

Determination of HBsAg and HBeAg

The content of HBsAg and HBeAg is detected by an enzyme-labeling instrument according to the Antu HBsAg ELISA kit and the Antu HBeAg ELISA kit specification.

Dose response curve

The HBsAg inhibition rate (%) was (1-HBsAg value of sample/HBsAg value of DMSO control group) × 100HBeAg inhibition rate (%) (1-HBeAg value of sample/HBeAg value of DMSO control group) × 100Analysis of results

As shown in fig. 3 and 4, wherein fig. 3 is an EC50 curve for inhibiting HBsAg in HepG2-NTCP cells; FIG. 4 is an EC50 curve for HBeAg inhibition in HepG2-NTCP cells. In the HepG2-NTCP assay, compounds 1 and 2 had a dose-dependent inhibitory effect on extracellular HBsAg and HBeAg. As a control, ETV had no significant inhibition of both HBsAg and HBeAg.

Claims

1. The fatty acid synthase inhibitor shown in the formula (I) or the formula (II), and the pharmaceutically acceptable salt, ester or stereoisomer thereof are applied to the preparation of anti-hepatitis B virus drugs,

2. the use according to claim 1, wherein the use comprises the use of a fatty acid synthase inhibitor of formula (I) or formula (II), a pharmaceutically acceptable salt, ester or stereoisomer thereof, in combination with one or more other anti-hepatitis b virus agent.

3. The use according to claim 2, wherein the other anti-hepatitis B virus agent is selected from one or more of an HBV vaccine, an HBV DNA polymerase inhibitor, an immunomodulator, a TOLL-like receptor modulator, an interferon alpha receptor ligand, a hepatitis B surface antigen inhibitor, a cyclophilin inhibitor, an HBV viral entry inhibitor, an antisense oligonucleotide targeting viral mRNA, a short interfering RNA and ddRNAi endonuclease modulator, a ribonucleotide reductase inhibitor, an HBV E antigen inhibitor, a covalently closed circular DNA inhibitor, a farnesoid X receptor agonist, an HBV antibody, a CCR2 chemokine antagonist, a retinoic acid inducible gene 1 agonist, an NOD2 agonist, a PD-1 inhibitor, a PD-L1 inhibitor, a KDM inhibitor and an HBV replication inhibitor.

4. The use according to claim 3, wherein the HBV DNA polymerase inhibitor is entecavir and/or tenofovir;

the PD-1 inhibitor is selected from one or more of nivolumab, pembrolizumab, pidilizumab, BGB-108, caprolizumab, PDR-001, saralazumab, IBI-308, gemipizumab, galizumab, sidlizumab, ti lelizumab, BCD-100, sibilizumab, Zimberelimab, Balstimab and doslizumab;

the PD-L1 inhibitor is selected from one or more of Abiralizumab, Avermezumab, BGB-A333, Devolumab, CX-072, GX-P2, Envolumab, GS-4224 and INCB 086550;

the farnesoid X receptor agonist is selected from one or more of AKN-083, Cilofexor, EDP-305, EYP-001, MET-409, Terns-101 and Tropifexor;

the interferon is peroxin;

the antisense oligonucleotide is Ionis-HBVRx and/or Ionis-HBV-LRx;

the short interfering RNA is selected from one or more of JNJ-3989, Vir-2218 and DCR-HBVS;

the capsid inhibitor is selected from one or more of ABI-H0731, ABI-H2158, ABI-H3733, CB-HBV-001, JNJ-6379, JNJ-0440, QL-007, RG-7907 and RO 7049389.

5. The use according to claim 3, wherein the other anti-HBV agent is selected from one or more of entecavir, tenofovir, entinostumab and pirocin.

6. A pharmaceutical composition for treating or preventing hepatitis B comprises a therapeutically effective amount of a fatty acid synthase inhibitor shown in formula (I) or formula (II) or a pharmaceutically acceptable salt, ester or stereoisomer thereof, one or more other anti-hepatitis B virus agents and pharmaceutically acceptable auxiliary materials,

7. the pharmaceutical composition of claim 6, wherein said other anti-hepatitis B virus agent is selected from one or more of an HBV vaccine, an HBV DNA polymerase inhibitor, an immunomodulator, a TOLL-like receptor modulator, an interferon alpha receptor ligand, a hepatitis B surface antigen inhibitor, a cyclophilin inhibitor, an HBV viral entry inhibitor, an antisense oligonucleotide targeting viral mRNA, short interfering RNA and ddRNAi endonuclease modulators, a ribonucleotide reductase inhibitor, an HBV E antigen inhibitor, a covalently closed circular DNA inhibitor, a farnesoid X receptor agonist, an HBV antibody, a CCR2 chemokine antagonist, a retinoic acid inducible gene 1 agonist, an NOD2 agonist, a PD-1 inhibitor, a PD-L1 inhibitor, a KDM inhibitor and an HBV replication inhibitor.

8. The pharmaceutical composition according to claim 7, wherein the HBV DNA polymerase inhibitor is entecavir and/or tenofovir;

the interferon is peroxin;

the antisense oligonucleotide is Ionis-HBVRx and/or Ionis-HBV-LRx;

9. The pharmaceutical composition according to claim 7, wherein the other anti-HBV agent is selected from one or more of entecavir, tenofovir, entillizumab, and pyroxin.